CN100404504C - Preparation process of 3,3-imyl butyrolactam - Google Patents
Preparation process of 3,3-imyl butyrolactam Download PDFInfo
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- CN100404504C CN100404504C CNB2006100519108A CN200610051910A CN100404504C CN 100404504 C CN100404504 C CN 100404504C CN B2006100519108 A CNB2006100519108 A CN B2006100519108A CN 200610051910 A CN200610051910 A CN 200610051910A CN 100404504 C CN100404504 C CN 100404504C
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- butyrolactam
- pentylidene
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Abstract
The present invention discloses a method for preparing 3, 3-pentylidene butyrolactam, which comprises: after 1, 1-monoamide cyclohexyl biacetate is added to alkali solution, hypochlorite is added to the alkali solution drop by drop for reaction; excessive hypochlorite is decomposed by using sulfite or bisulfite as a reducing agent; after the pH value is regulated by using inorganic acid, the mixture is treated with flow back reaction to obtain 3, 3-pentylidene butyrolactam. The yield of the 3, 3-pentylidene butyrolactam prepared by the method of the present invention is more than 92%, the purity is more than 99%, and raw material is inexpensive and is easy to obtain. In addition, technological processes are carried out in an environmental-protection water phase without using organic solvent. Thus, the operation is simple and convenient, and the method of the present invention is suitable for industrialized production.
Description
Technical field
The present invention relates to a kind of 3, the preparation method of 3-pentylidene butyrolactam, with 1,1-cyclohexanediacetic acid monoamide is a starting raw material.
Background technology
3, (have another name called: 2-azepine-spiral shell-[4,5]-3-decanone), have the chemical structure of formula (I), be a kind of important intermediate of preparation bulk drug gabapentin to 3-pentylidene butyrolactam, can make gabapentin through hydrolysis reaction.
A kind of preparation 3 is disclosed in the U.S. Pat 5091567, the synthetic method of 3-pentylidene butyrolactam, form the cyclohexylidene acid esters by pimelinketone and phosphonic acid ester Wittig reagent react, obtain 3 with Nitromethane 99Min. condensation, shortening, cyclization again, 3-pentylidene butyrolactam, this method is used Wittig reagent, 10%Pd-C and the inflammable and explosive hydrogen of the big Nitromethane 99Min. of toxicity, costliness, and its reaction process is used a large amount of multiple organic solvents, this method trivial operations, pollute big, the cost height can't be realized suitability for industrialized production.
Disclose among U.S. Pat 5068413 and the US5319135 by pimelinketone and diethyl malonate or ethyl cyanoacetate condensation, through shortening, add reactions such as thermal decarboxylation, cyclization and make 3, the method of 3-pentylidene butyrolactam, these class methods are owing to using hypertoxic sodium cyanide and hydrogen chloride gas to pollute bigger, and reactions steps is long, yield is on the low side, to the operational requirement height, big difficulty is arranged in actual production process.
Disclose by 1 in the U.S. Pat 4152326,1-cyclohexanediacetic acid acid anhydride and oxammonium hydrochloride, benzene sulfonyl chloride and sodium ethylate make 3 through the Lossen rearrangement reaction, the method for 3-pentylidene butyrolactam, but yield is lower.
Disclose among the Chinese patent application CN1727329A by the methylene radical hexanaphthene in ether solvent with zinc powder, the trichoroacetic chloride reaction obtains 1,1-dichloro spiral shell [3,5]-methyl n-heptyl ketone, obtain 3 with zinc powder reaction and Beckmann rearrangement again, the method of 3-pentylidene butyrolactam, but this method is polluted greatly, raw material sources are difficult, also is not suitable for suitability for industrialized production.
Indian Sircar is in nineteen twenty-eight (J.Ind.Chem.Soc.1928,5,549; CA192923818) reported with 1 that 1-cyclohexanediacetic acid monoamide (II) is a raw material, in bromine and aqueous sodium hydroxide solution, formed sodium hypobromite and carry out the Hofmann rearrangement reaction that yield is 46%.Reaction formula is as follows:
Use the identical reagent Br of Sircar among the patent WO2004046108 in the disclosed method
2/ NaOH/H
2O has carried out process modification to the Hofmann reaction conditions, and yield brings up to 80.7%.But the sodium hypobromite that this technology is used is difficult to obtain from commodity, must use bromine in a large number, and toxicity is big, and environmental pollution is serious.
Summary of the invention
The invention provides a kind of easy and simple to handle, cost is low, yield is high preparation 3, the method for 3-pentylidene butyrolactam.
A kind of 3, the preparation method of 3-pentylidene butyrolactam, with 1,1-cyclohexanediacetic acid monoamide is a starting raw material, comprises the steps:
(1) with 1,1-cyclohexyl oxalic acid monoamide joins in the aqueous solution of alkali, and temperature is lower than 50 ℃ and drips hypochlorite, reacts after dropwising.
Described alkali is NaOH, KOH, NH
3.H
2O or other water miscible alkali metal hydroxide, preferred sodium hydroxide or potassium hydroxide.The solution quality percentage concentration of alkali is 5～30%.
Described hypochlorite is the alkaline metal hypochlorite, preferred clorox.The available chlorine content of hypochlorite is 5～20%.
1, the mol ratio of 1-cyclohexyl oxalic acid monoamide and alkali is 1: 2～10, preferred 1: 3～6; With the mole proportioning of hypochlorite be 1: 1.0～3.0, preferred 1: 1.0～1.5.
(2) add the hypochlorite that S-WAT or sodium bisulfite are made the reductive agent decomposing excessive;
(3) add inorganic acid for adjusting pH value 7.0～13, and obtain containing 3, the reaction solution of 3-pentylidene butyrolactam in 30～120 ℃ of reactions.
Described mineral acid is hydrochloric acid, Hydrogen bromide, sulfuric acid or phosphoric acid, preferred hydrochloric acid or sulfuric acid.
In step (3), generated product 3,3-pentylidene butyrolactam, further aftertreatment as required, post-treating method has following two kinds:
Method one be the reaction solution that will obtain in the described step (3) directly cooling or concentrate after cooling again, 3,3-pentylidene butyrolactam is separated out from the aqueous solution, filters, dry white crystal product 3,3-pentylidene butyrolactam.
Method two is that the reaction solution that will obtain in the described step (3) is cooled to certain temperature, and with organic solvent extraction, layering, organic layer distillating recovering solvent, the residue cooling obtains white or off-white color crystalline product 3,3-pentylidene butyrolactam.
Described organic solvent is aromatic hydrocarbon such as benzene,toluene,xylene or hydrochloric ether such as methylene dichloride, ethylene dichloride, chloroform, preferred methylene dichloride or toluene.
According to the method for the invention prepare 3,3-pentylidene butyrolactam and hydrochloric acid hydrolysis can obtain high purity, meet the gabapentin that pharmaceutical grade requires.
Use the inventive method, reaction yield is up to 97%, and purity＞99% (uses Br with existing similar approach WO2004046108
2/ NaOH/H
2O, yield 80.7%) relatively, yield obviously improves.
1 of the inventive method employing, 1-cyclohexanediacetic acid monoamide raw material can obtain the patent of invention ZL00128111.9 of Chinese patent mandate by the applicant, denomination of invention is that " 1; preparation method of 1-cyclohexanediacetic acid monoamide " disclosed method is prepared, productive rate height, production cost are low, clorox is directed to technical grade simultaneously, raw material is cheap and easy to get, entire reaction is easy and simple to handle, technological process is carried out at the aqueous phase of environmental protection, can be not with an organic solvent, the product purity height is suitable for suitability for industrialized production.
Embodiment
The strength of solution of the hydrochloric acid of mentioning among the embodiment, sodium hydroxide, clorox is mass percent concentration.
Embodiment 1
In 2000 liters of reactors, add 420 kilogram 30% aqueous sodium hydroxide solution (industrial lye), 350 premium on currency, be cooled to 10～20 ℃, drop into 160 kilogram 1,1-cyclohexanediacetic acid monoamide stirs, be cooled to 0～15 ℃ again, drip 630 kilogram 11.3% aqueous sodium hypochlorite solution, dropwise, be warming up to 40～50 ℃ of reactions 3 hours, the clorox of sodium bisulfite decomposing excessive, and check with starch potassium iodide paper.Add 30% technical hydrochloric acid and transfer pH=11～12, be warming up to 100～105 ℃ of back flow reaction 2～3 hours, backflow is switched to distillation, steam water 300～400 premium on currency, be cooled to 0～5 ℃, centrifugal, a small amount of frozen water washing, dry, vacuum-drying gets white crystal product 3,115.5 kilograms of 3-pentylidene butyrolactams, yield 93.8%, 90～92 ℃ of fusing points, purity 99.7%.
Embodiment 2
In 2000 milliliters of reaction flasks, the aqueous sodium hydroxide solution (industrial lye) that adds 420 grams 30%, 350 ml waters are cooled to 10～20 ℃, add 160 grams 1,1-cyclohexanediacetic acid monoamide, stir, be cooled to 0～15 ℃, drip 675 grams, 10.7% aqueous sodium hypochlorite solution, dropwise, be warming up to 40～45 ℃ of reactions 3 hours, add the clorox of sodium bisulfite decomposing excessive, add 30% hydrochloric acid again and transfer pH=11～12, be warming up to 100～105 ℃ of back flow reaction 3 hours, be cooled to 0～5 ℃, filter, a small amount of frozen water washing, vacuum-drying, get white crystal product 3,3-pentylidene butyrolactam 113.6 grams, yield 92.3%, 90～92 ℃ of fusing points, purity 99.8%.
Embodiment 3
In 2000 milliliters of reaction flasks, add the aqueous sodium hydroxide solution (industrial lye) of 420 grams 30%, 350 ml waters, be cooled to 10～20 ℃, add 160 grams 1,1-cyclohexanediacetic acid monoamide stirs, be cooled to 0～15 ℃, drip 680 grams, 10.5% aqueous sodium hypochlorite solution, dropwise, be warming up to 40～50 ℃ of reactions 3 hours, the clorox that adds the sodium bisulfite decomposing excessive, add 30% hydrochloric acid again and transfer pH=11～12, be warming up to 100～105 ℃ of back flow reaction 3 hours, be cooled to 50～60 ℃, add the toluene extraction, branch vibration layer, toluene is reclaimed in the organic phase underpressure distillation, inclines while hot to, vacuum-drying, get off-white color crystalline product 3,3-pentylidene butyrolactam 119.5 grams, yield 97.1%, 89～91 ℃ of fusing points, purity 99.3%.
Embodiment 4
In 2000 milliliters of reaction flasks, add 630 ml waters, 170 gram potassium hydroxide, be cooled to 10～20 ℃, add 160 grams 1,1-cyclohexanediacetic acid monoamide stirs, be cooled to 0～10 ℃, drip 685 grams, 10.5% aqueous sodium hypochlorite solution, dropwise, be warming up to 40～45 ℃ of reactions 2 hours, the clorox that adds the sodium bisulfite decomposing excessive, add 30% hydrochloric acid again and transfer pH=11～13, be warming up to 100～105 ℃ of back flow reaction 3 hours, be cooled to 50～60 ℃, add the toluene extraction, branch vibration layer, toluene is reclaimed in the organic phase underpressure distillation, inclines while hot to, vacuum-drying, get off-white color crystalline product 3,3-pentylidene butyrolactam 113.9 grams, yield 92.5%, 89～91 ℃ of fusing points, purity 99.5%.
Reference examples
The example 1 of patent WO2004046108 is referred to the present patent application in contrast.
Be added dropwise in 1 kg of hydrogen sodium oxide and the 7 premium on currency solution in-5～0 ℃ of bromine with 0.824 kilogram (5.15 moles), 45～90 minutes dropping time, solution was in-5～0 ℃ of reaction 30 minutes.In-5～0 ℃, with 1 kilogram of (5.02 mole) 1,1-cyclohexyl oxalic acid monoamide is added dropwise in the reaction solution, and the dropping time is more than 3 hours, stirring reaction 1 hour.Reaction solution slowly was warming up to 80～85 ℃ in 4 hours, and in this temperature restir reaction 6 hours, was cooled to 40 ℃ and extracts secondary with toluene, water layer is warming up to 80～85 ℃ of reactions 6 hours again, is cooled to 40 ℃, extracts secondary with toluene again, the combining methylbenzene layer is used decolorizing with activated carbon, filters, filtrate washing secondary, toluene is reclaimed in 60 ℃ of vacuum distillings, obtains white crystal 3,3-pentylidene butyrolactam 0.62 gram, yield 80.7%, 88～90 ℃ of fusing points, purity＞99%.
The contrast conclusion: compare with technology of the present invention, use bromine in the reference examples, toxicity is big, and environmental pollution is serious, and yield has only 80.7%, well below the yield of technology of the present invention.
Claims (10)
1. one kind 3, the preparation method of 3-pentylidene butyrolactam, with 1,1-cyclohexanediacetic acid monoamide is a starting raw material, comprises the steps:
(1) with 1,1-cyclohexyl oxalic acid monoamide joins in the aqueous solution of alkali, and temperature is lower than 50 ℃ and drips hypochlorite down, reacts after dropwising;
(2) add the hypochlorite that sulphite or hydrosulphite are made the reductive agent decomposing excessive;
(3) add inorganic acid for adjusting pH value 7～13, be warming up to 30～120 ℃ of reactions down, obtain containing 3, the reaction solution of 3-pentylidene butyrolactam.
2. preparation method according to claim 1 is characterized in that: the described alkali of step (1) is NaOH, KOH, NH
3H
2O or other water miscible alkali metal hydroxide.
3. preparation method according to claim 1 is characterized in that: the aqueous solution mass percent concentration of the described alkali of step (1) is 5～30%.
4. preparation method according to claim 1 is characterized in that: step (1) is described 1, and the mol ratio of 1-cyclohexyl oxalic acid monoamide and alkali is 1: 2～10.
5. preparation method according to claim 1 is characterized in that: the described hypochlorite of step (1) is that available chlorine content is 5～20% alkaline metal hypochlorite.
6. preparation method according to claim 5 is characterized in that: described alkaline metal hypochlorite is a clorox.
7. preparation method according to claim 1 is characterized in that: step (1) is described 1, and the mol ratio of 1-cyclohexanediacetic acid monoamide and hypochlorite is 1: 1.0～3.0.
8. preparation method according to claim 1 is characterized in that: the described mineral acid of step (3) is hydrochloric acid, Hydrogen bromide, sulfuric acid or phosphoric acid.
9. preparation method according to claim 1 is characterized in that: also comprise the direct or concentrated postcooling of the resulting reaction solution of step (3), separate out 3 from the aqueous solution, 3-pentylidene butyrolactam.
10. preparation method according to claim 1 is characterized in that: also comprise the cooling of the resulting reaction solution of step (3), add the extraction of aromatic hydrocarbon or chlorohydrocarbon organic solvent, separate organic phase, the distillation organic solvent, cool off 3,3-pentylidene butyrolactam.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2006100519108A CN100404504C (en) | 2006-06-12 | 2006-06-12 | Preparation process of 3,3-imyl butyrolactam |
| US11/457,023 US7442834B2 (en) | 2006-06-12 | 2006-07-12 | Process suitable for industrial scale production of gabapentin |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2006100519108A CN100404504C (en) | 2006-06-12 | 2006-06-12 | Preparation process of 3,3-imyl butyrolactam |
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| Publication Number | Publication Date |
|---|---|
| CN1861579A CN1861579A (en) | 2006-11-15 |
| CN100404504C true CN100404504C (en) | 2008-07-23 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB2006100519108A Expired - Fee Related CN100404504C (en) | 2006-06-12 | 2006-06-12 | Preparation process of 3,3-imyl butyrolactam |
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Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104402796A (en) * | 2014-11-26 | 2015-03-11 | 太仓运通生物化工有限公司 | Preparation method for 3,3-amylidene butyrolactam |
| CN104402744A (en) * | 2014-11-28 | 2015-03-11 | 太仓运通生物化工有限公司 | Preparation method for gabapentin |
| CN107011197B (en) * | 2017-04-21 | 2019-05-31 | 清华大学 | A method of continuously preparing Gabapentin |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5068413A (en) * | 1989-08-25 | 1991-11-26 | Godecke Aktiengesellschaft | Process for the preparation of cyclic amino acids and intermediates useful in the process |
| US5091567A (en) * | 1989-08-25 | 1992-02-25 | Godecke Aktiengesellschaft | Process for the preparation of 1-aminomethyl-1-cyclohexaneacetic acid |
| US5319135A (en) * | 1989-08-25 | 1994-06-07 | Warner-Lambert Company | Process for cyclic amino acid anticonvulsant compounds |
| WO2004046108A1 (en) * | 2002-11-20 | 2004-06-03 | Hikal Ltd. | An improved process for the preparation of gabalactam |
| CN1727329A (en) * | 2004-07-28 | 2006-02-01 | 长春吉大天元化学技术股份有限公司 | New method for synthesizing Gabapentin hydrochloride |
-
2006
- 2006-06-12 CN CNB2006100519108A patent/CN100404504C/en not_active Expired - Fee Related
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5068413A (en) * | 1989-08-25 | 1991-11-26 | Godecke Aktiengesellschaft | Process for the preparation of cyclic amino acids and intermediates useful in the process |
| US5091567A (en) * | 1989-08-25 | 1992-02-25 | Godecke Aktiengesellschaft | Process for the preparation of 1-aminomethyl-1-cyclohexaneacetic acid |
| US5319135A (en) * | 1989-08-25 | 1994-06-07 | Warner-Lambert Company | Process for cyclic amino acid anticonvulsant compounds |
| WO2004046108A1 (en) * | 2002-11-20 | 2004-06-03 | Hikal Ltd. | An improved process for the preparation of gabalactam |
| CN1727329A (en) * | 2004-07-28 | 2006-02-01 | 长春吉大天元化学技术股份有限公司 | New method for synthesizing Gabapentin hydrochloride |
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